ADMINISTRATIVE and CORRESPONDENCE DOCUMENTS · Page 3 NDA# 020747 Actiq NDA# 022266 Onsolis NDA# 022510 Abstral NDA# 021947 Fentora NDA# 016619 Sublimaze NDA# 021338 Ionsys 2. Combination

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER: 022569Orig1s000

ADMINISTRATIVE and CORRESPONDENCE DOCUMENTS

Page 1

EXCLUSIVITY SUMMARY

NDA # 022569 SUPPL # HFD # 170

Trade Name Lazanda Generic Name fentanyl Applicant Name Archimedes Development Ltd Approval Date, If Known June 30, 2011 PART I IS AN EXCLUSIVITY DETERMINATION NEEDED? 1. An exclusivity determination will be made for all original applications, and all efficacy supplements. Complete PARTS II and III of this Exclusivity Summary only if you answer "yes" to one or more of the following questions about the submission.

a) Is it a 505(b)(1), 505(b)(2) or efficacy supplement? YES NO If yes, what type? Specify 505(b)(1), 505(b)(2), SE1, SE2, SE3,SE4, SE5, SE6, SE7, SE8 505(b)(2)

c) Did it require the review of clinical data other than to support a safety claim or change in labeling related to safety? (If it required review only of bioavailability or bioequivalence data, answer "no.")

YES NO

If your answer is "no" because you believe the study is a bioavailability study and, therefore, not eligible for exclusivity, EXPLAIN why it is a bioavailability study, including your reasons for disagreeing with any arguments made by the applicant that the study was not simply a bioavailability study.

If it is a supplement requiring the review of clinical data but it is not an effectiveness supplement, describe the change or claim that is supported by the clinical data:

d) Did the applicant request exclusivity?

Reference ID: 2968184

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YES NO If the answer to (d) is "yes," how many years of exclusivity did the applicant request?

3 years

e) Has pediatric exclusivity been granted for this Active Moiety? YES NO

If the answer to the above question in YES, is this approval a result of the studies submitted in response to the Pediatric Written Request? no IF YOU HAVE ANSWERED "NO" TO ALL OF THE ABOVE QUESTIONS, GO DIRECTLY TO THE SIGNATURE BLOCKS AT THE END OF THIS DOCUMENT. 2. Is this drug product or indication a DESI upgrade?

YES NO IF THE ANSWER TO QUESTION 2 IS "YES," GO DIRECTLY TO THE SIGNATURE BLOCKS ON PAGE 8 (even if a study was required for the upgrade). PART II FIVE-YEAR EXCLUSIVITY FOR NEW CHEMICAL ENTITIES (Answer either #1 or #2 as appropriate) 1. Single active ingredient product. Has FDA previously approved under section 505 of the Act any drug product containing the same active moiety as the drug under consideration? Answer "yes" if the active moiety (including other esterified forms, salts, complexes, chelates or clathrates) has been previously approved, but this particular form of the active moiety, e.g., this particular ester or salt (including salts with hydrogen or coordination bonding) or other non-covalent derivative (such as a complex, chelate, or clathrate) has not been approved. Answer "no" if the compound requires metabolic conversion (other than deesterification of an esterified form of the drug) to produce an already approved active moiety.

YES NO If "yes," identify the approved drug product(s) containing the active moiety, and, if known, the NDA #(s).

NDA# 019813 Duragesic


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NDA# 020747 Actiq

NDA# 022266 Onsolis

NDA# 022510 Abstral

NDA# 021947 Fentora

NDA# 016619 Sublimaze

NDA# 021338 Ionsys

2. Combination product. If the product contains more than one active moiety(as defined in Part II, #1), has FDA previously approved an application under section 505 containing any one of the active moieties in the drug product? If, for example, the combination contains one never-before-approved active moiety and one previously approved active moiety, answer "yes." (An active moiety that is marketed under an OTC monograph, but that was never approved under an NDA, is considered not previously approved.)

YES NO If "yes," identify the approved drug product(s) containing the active moiety, and, if known, the NDA #(s). NDA#

NDA#

NDA#

IF THE ANSWER TO QUESTION 1 OR 2 UNDER PART II IS "NO," GO DIRECTLY TO THE SIGNATURE BLOCKS ON PAGE 8. (Caution: The questions in part II of the summary should only be answered “NO” for original approvals of new molecular entities.) IF “YES,” GO TO PART III. PART III THREE-YEAR EXCLUSIVITY FOR NDAs AND SUPPLEMENTS To qualify for three years of exclusivity, an application or supplement must contain "reports of new clinical investigations (other than bioavailability studies) essential to the approval of the application and conducted or sponsored by the applicant." This section should be completed only if the answer to PART II, Question 1 or 2 was "yes."


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1. Does the application contain reports of clinical investigations? (The Agency interprets "clinical investigations" to mean investigations conducted on humans other than bioavailability studies.) If the application contains clinical investigations only by virtue of a right of reference to clinical investigations in another application, answer "yes," then skip to question 3(a). If the answer to 3(a) is "yes" for any investigation referred to in another application, do not complete remainder of summary for that investigation.

YES NO IF "NO," GO DIRECTLY TO THE SIGNATURE BLOCKS ON PAGE 8. 2. A clinical investigation is "essential to the approval" if the Agency could not have approved the application or supplement without relying on that investigation. Thus, the investigation is not essential to the approval if 1) no clinical investigation is necessary to support the supplement or application in light of previously approved applications (i.e., information other than clinical trials, such as bioavailability data, would be sufficient to provide a basis for approval as an ANDA or 505(b)(2) application because of what is already known about a previously approved product), or 2) there are published reports of studies (other than those conducted or sponsored by the applicant) or other publicly available data that independently would have been sufficient to support approval of the application, without reference to the clinical investigation submitted in the application.

(a) In light of previously approved applications, is a clinical investigation (either conducted by the applicant or available from some other source, including the published literature) necessary to support approval of the application or supplement?

YES NO

If "no," state the basis for your conclusion that a clinical trial is not necessary for approval AND GO DIRECTLY TO SIGNATURE BLOCK ON PAGE 8:

(b) Did the applicant submit a list of published studies relevant to the safety and effectiveness of this drug product and a statement that the publicly available data would not independently support approval of the application?

YES NO (1) If the answer to 2(b) is "yes," do you personally know of any reason to disagree with the applicant's conclusion? If not applicable, answer NO.

YES NO

If yes, explain:

(2) If the answer to 2(b) is "no," are you aware of published studies not conducted or


Page 5

sponsored by the applicant or other publicly available data that could independently demonstrate the safety and effectiveness of this drug product?

YES NO

If yes, explain:

(c) If the answers to (b)(1) and (b)(2) were both "no," identify the clinical investigations submitted in the application that are essential to the approval:

Lazanda was tested in a single adequate and well-controlled study [Study CP043/06/FCNS] using what has become the standard design for these products. Opioid-tolerant cancer patients with breakthrough pain complete an open-label dose-finding period. If a successful dose (adequate balance between analgesia and tolerability) is found, the patient enters a 10-period, double-blind, placebo-controlled period. Sequential doses (7 active and 3 placebo, distributed randomly) are administered upon the start of an episode of breakthrough pain and the pain intensity is graded at close intervals. Episodes treated with FCNS had a statistically significantly larger difference in the summed pain intensity compared to placebo.

Studies comparing two products with the same ingredient(s) are considered to be bioavailability studies for the purpose of this section. 3. In addition to being essential, investigations must be "new" to support exclusivity. The agency interprets "new clinical investigation" to mean an investigation that 1) has not been relied on by the agency to demonstrate the effectiveness of a previously approved drug for any indication and 2) does not duplicate the results of another investigation that was relied on by the agency to demonstrate the effectiveness of a previously approved drug product, i.e., does not redemonstrate something the agency considers to have been demonstrated in an already approved application.

a) For each investigation identified as "essential to the approval," has the investigation been relied on by the agency to demonstrate the effectiveness of a previously approved drug product? (If the investigation was relied on only to support the safety of a previously approved drug, answer "no.")

Investigation #1 YES NO



Page 6

If you have answered "yes" for one or more investigations, identify each such investigation and the NDA in which each was relied upon:

b) For each investigation identified as "essential to the approval", does the investigation duplicate the results of another investigation that was relied on by the agency to support the effectiveness of a previously approved drug product?



If you have answered "yes" for one or more investigation, identify the NDA in which a similar investigation was relied on:

c) If the answers to 3(a) and 3(b) are no, identify each "new" investigation in the application or supplement that is essential to the approval (i.e., the investigations listed in #2(c), less any that are not "new"):

Study CP043/06/FCNS, described above

4. To be eligible for exclusivity, a new investigation that is essential to approval must also have been conducted or sponsored by the applicant. An investigation was "conducted or sponsored by" the applicant if, before or during the conduct of the investigation, 1) the applicant was the sponsor of the IND named in the form FDA 1571 filed with the Agency, or 2) the applicant (or its predecessor in interest) provided substantial support for the study. Ordinarily, substantial support will mean providing 50 percent or more of the cost of the study.

a) For each investigation identified in response to question 3(c): if the investigation was carried out under an IND, was the applicant identified on the FDA 1571 as the sponsor?

Investigation #1 ! !

IND # 070854 YES ! NO ! Explain:

Investigation #2 !


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! IND # YES ! NO ! Explain:

(b) For each investigation not carried out under an IND or for which the applicant was not identified as the sponsor, did the applicant certify that it or the applicant's predecessor in interest provided substantial support for the study?

Investigation #1 !

! YES ! NO Explain: ! Explain:

Investigation #2 !

! YES ! NO Explain: ! Explain:

(c) Notwithstanding an answer of "yes" to (a) or (b), are there other reasons to believe that the applicant should not be credited with having "conducted or sponsored" the study? (Purchased studies may not be used as the basis for exclusivity. However, if all rights to the drug are purchased (not just studies on the drug), the applicant may be considered to have sponsored or conducted the studies sponsored or conducted by its predecessor in interest.)

YES NO

If yes, explain:

================================================================= Name of person completing form: Matthew W. Sullivan Title: Senior Regulatory Project Manager Date: June 28, 2011


Page 8

Name of Office/Division Director signing form: Bob A. Rappaport Title: Director, Division of Anesthesia, Analgesia, and Addiction Products Form OGD-011347; Revised 05/10/2004; formatted 2/15/05


---------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signedelectronically and this page is the manifestation of the electronicsignature.---------------------------------------------------------------------------------------------------------/s/----------------------------------------------------

MATTHEW W SULLIVAN06/30/2011

BOB A RAPPAPORT06/30/2011



NDA/BLA # 022569 Page 4

Version: 4/21/11

• [505(b)(2) applications] For each paragraph IV certification, based on the

questions below, determine whether a 30-month stay of approval is in effect due to patent infringement litigation.

Answer the following questions for each paragraph IV certification:

(1) Have 45 days passed since the patent owner’s receipt of the applicant’s

notice of certification?

(Note: The date that the patent owner received the applicant’s notice of certification can be determined by checking the application. The applicant is required to amend its 505(b)(2) application to include documentation of this date (e.g., copy of return receipt or letter from recipient acknowledging its receipt of the notice) (see 21 CFR 314.52(e))).

If “Yes,” skip to question (4) below. If “No,” continue with question (2).

(2) Has the patent owner (or NDA holder, if it is an exclusive patent licensee)

submitted a written waiver of its right to file a legal action for patent infringement after receiving the applicant’s notice of certification, as provided for by 21 CFR 314.107(f)(3)?

If “Yes,” there is no stay of approval based on this certification. Analyze the next paragraph IV certification in the application, if any. If there are no other paragraph IV certifications, skip the rest of the patent questions. If “No,” continue with question (3).

(3) Has the patent owner, its representative, or the exclusive patent licensee filed a lawsuit for patent infringement against the applicant?

(Note: This can be determined by confirming whether the Division has received a written notice from the (b)(2) applicant (or the patent owner or its representative) stating that a legal action was filed within 45 days of receipt of its notice of certification. The applicant is required to notify the Division in writing whenever an action has been filed within this 45-day period (see 21 CFR 314.107(f)(2))).

If “No,” the patent owner (or NDA holder, if it is an exclusive patent licensee) has until the expiration of the 45-day period described in question (1) to waive its right to bring a patent infringement action or to bring such an action. After the 45-day period expires, continue with question (4) below.

(4) Did the patent owner (or NDA holder, if it is an exclusive patent licensee)

submit a written waiver of its right to file a legal action for patent infringement within the 45-day period described in question (1), as provided for by 21 CFR 314.107(f)(3)?

If “Yes,” there is no stay of approval based on this certification. Analyze the next paragraph IV certification in the application, if any. If there are no other paragraph IV certifications, skip to the next section below (Summary Reviews). If “No,” continue with question (5).

Yes No

Yes No

Yes No

Yes No


NDA/BLA # 022569 Page 11

Version: 4/21/11

Appendix to Action Package Checklist An NDA or NDA supplemental application is likely to be a 505(b)(2) application if:

(1) It relies on published literature to meet any of the approval requirements, and the applicant does not have a written right of reference to the underlying data. If published literature is cited in the NDA but is not necessary for approval, the inclusion of such literature will not, in itself, make the application a 505(b)(2) application.

(2) Or it relies for approval on the Agency's previous findings of safety and efficacy for a listed drug product and the applicant does not own or have right to reference the data supporting that approval.

(3) Or it relies on what is "generally known" or "scientifically accepted" about a class of products to support the safety or effectiveness of the particular drug for which the applicant is seeking approval. (Note, however, that this does not mean any reference to general information or knowledge (e.g., about disease etiology, support for particular endpoints, methods of analysis) causes the application to be a 505(b)(2) application.)

Types of products for which 505(b)(2) applications are likely to be submitted include: fixed-dose combination drug products (e.g., heart drug and diuretic (hydrochlorothiazide) combinations); OTC monograph deviations(see 21 CFR 330.11); new dosage forms; new indications; and, new salts. An efficacy supplement can be either a (b)(1) or a (b)(2) regardless of whether the original NDA was a (b)(1) or a (b)(2). An efficacy supplement is a 505(b)(1) supplement if the supplement contains all of the information needed to support the approval of the change proposed in the supplement. For example, if the supplemental application is for a new indication, the supplement is a 505(b)(1) if:

(1) The applicant has conducted its own studies to support the new indication (or otherwise owns or has right of reference to the data/studies).

(2) And no additional information beyond what is included in the supplement or was embodied in the finding of safety and effectiveness for the original application or previously approved supplements is needed to support the change. For example, this would likely be the case with respect to safety considerations if the dose(s) was/were the same as (or lower than) the original application.

(3) And all other “criteria” are met (e.g., the applicant owns or has right of reference to the data relied upon for approval of the supplement, the application does not rely for approval on published literature based on data to which the applicant does not have a right of reference).

An efficacy supplement is a 505(b)(2) supplement if:

(1) Approval of the change proposed in the supplemental application would require data beyond that needed to support our previous finding of safety and efficacy in the approval of the original application (or earlier supplement), and the applicant has not conducted all of its own studies for approval of the change, or obtained a right to reference studies it does not own. For example, if the change were for a new indication AND a higher dose, we would likely require clinical efficacy data and preclinical safety data to approve the higher dose. If the applicant provided the effectiveness data, but had to rely on a different listed drug, or a new aspect of a previously cited listed drug, to support the safety of the new dose, the supplement would be a 505(b)(2).

(2) Or the applicant relies for approval of the supplement on published literature that is based on data that the applicant does not own or have a right to reference. If published literature is cited in the supplement but is not necessary for approval, the inclusion of such literature will not, in itself, make the supplement a 505(b)(2) supplement.

(3) Or the applicant is relying upon any data they do not own or to which they do not have right of reference. If you have questions about whether an application is a 505(b)(1) or 505(b)(2) application, consult with your ODE’s ADRA.





Version March 2009 page 2

INFORMATION PROVIDED VIA RELIANCE (LISTED DRUG OR LITERATURE)

2) List the information essential to the approval of the proposed drug that is provided by reliance

on our previous finding of safety and efficacy for a listed drug or by reliance on published literature. (If not clearly identified by the applicant, this information can usually be derived from annotated labeling.)

Source of information* (e.g., published literature, name of referenced product)

Information provided (e.g., pharmacokinetic data, or specific sections of labeling)

Actiq (NDA 020747) Multiple sections of labeling

*each source of information should be listed on separate rows 3) Reliance on information regarding another product (whether a previously approved product

or from published literature) must be scientifically appropriate. An applicant needs to provide a scientific “bridge” to demonstrate the relationship of the referenced and proposed products. Describe how the applicant bridged the proposed product to the referenced product(s). (Example: BA/BE studies)

Archimedes has conducted clinical pharmacokinetic, efficacy and safety data to support the new route of delivery (nasal), and to compare the bioavailability of fentanyl from Lazanda vs. Actiq.

RELIANCE ON PUBLISHED LITERATURE 4) (a) Regardless of whether the applicant has explicitly stated a reliance on published literature

to support their application, is reliance on published literature necessary to support the approval of the proposed drug product (i.e., the application cannot be approved without the published literature)?

YES NO If “NO,” proceed to question #5.

(b) Does any of the published literature necessary to support approval identify a specific (e.g., brand name) listed drug product?

YES NO If “NO”, proceed to question #5.

If “YES”, list the listed drug(s) identified by name and answer question #4(c).

(c) Are the drug product(s) listed in (b) identified by the applicant as the listed drug(s)? YES NO



RELIANCE ON LISTED DRUG(S) Reliance on published literature which identifies a specific approved (listed) drug constitutes

reliance on that listed drug. Please answer questions #5-9 accordingly.

5) Regardless of whether the applicant has explicitly referenced the listed drug(s), does the application rely on the finding of safety and effectiveness for one or more listed drugs (approved drugs) to support the approval of the proposed drug product (i.e., the application cannot be approved without this reliance)?

If “NO,” proceed to question #10. 6) Name of listed drug(s) relied upon, and the NDA/ANDA #(s). Please indicate if the applicant

explicitly identified the product as being relied upon (see note below):

Name of Drug NDA/ANDA # Did applicant specify reliance on the product? (Y/N)

Actiq 020747 Y

Applicants should specify reliance on the 356h, in the cover letter, and/or with their patent

certification/statement. If you believe there is reliance on a listed product that has not been explicitly identified as such by the applicant, please contact the (b)(2) review staff in the

Immediate Office, Office of New Drugs. 7) If this is a (b)(2) supplement to an original (b)(2) application, does the supplement rely upon

the same listed drug(s) as the original (b)(2) application? N/A YES NO

If this application is a (b)(2) supplement to an original (b)(1) application or not a supplemental application, answer “N/A”.

If “NO”, please contact the (b)(2) review staff in the Immediate Office, Office of New Drugs.

8) Were any of the listed drug(s) relied upon for this application: a) Approved in a 505(b)(2) application?

YES NO If “YES”, please list which drug(s).

Name of drug(s) approved in a 505(b)(2) application: Actiq

b) Approved by the DESI process?

YES NO If “YES”, please list which drug(s).

Name of drug(s) approved via the DESI process:

c) Described in a monograph? YES NO

YES NO



If “YES”, please list which drug(s).

Name of drug(s) described in a monograph:

d) Discontinued from marketing? YES NO

If “YES”, please list which drug(s) and answer question d) i. below. If “NO”, proceed to question #9.

Name of drug(s) discontinued from marketing:

i) Were the products discontinued for reasons related to safety or effectiveness? YES NO

(Information regarding whether a drug has been discontinued from marketing for reasons of safety or effectiveness may be available in the Orange Book. Refer to section 1.11 for an explanation, and section 6.1 for the list of discontinued drugs. If a determination of the reason for discontinuation has not been published in the Federal Register (and noted in the Orange Book), you will need to research the archive file and/or consult with the review team. Do not rely solely on any statements made by the sponsor.)

9) Describe the change from the listed drug(s) relied upon to support this (b)(2) application (for example, “This application provides for a new indication, otitis media” or “This application provides for a change in dosage form, from capsule to solution”).

This application provides a change in dosage form and route of administration, from transmucosal lozenge to nasal spray.

The purpose of the following two questions is to determine if there is an approved drug product that is equivalent or very similar to the product proposed for approval that should be referenced as a listed drug in the pending application. The assessment of pharmaceutical equivalence for a recombinant or biologically-derived product and/or protein or peptide product is complex. If you answered YES to question #1, proceed to question #12; if you answered NO to question #1, proceed to question #10 below. 10) (a) Is there a pharmaceutical equivalent(s) to the product proposed in the 505(b)(2)

application that is already approved (via an NDA or ANDA)?

(Pharmaceutical equivalents are drug products in identical dosage forms that: (1) contain identical amounts of the identical active drug ingredient, i.e., the same salt or ester of the same therapeutic moiety, or, in the case of modified release dosage forms that require a reservoir or overage or such forms as prefilled syringes where residual volume may vary, that deliver identical amounts of the active drug ingredient over the identical dosing period; (2) do not necessarily contain the same inactive ingredients; and (3) meet the identical compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times, and/or dissolution rates. (21 CFR 320.1(c)).

Note that for proposed combinations of one or more previously approved drugs, a pharmaceutical equivalent must also be a combination of the same drugs.



YES NO

If “NO” to (a) proceed to question #11. If “YES” to (a), answer (b) and (c) then proceed to question #12.

(b) Is the pharmaceutical equivalent approved for the same indication for which the 505(b)(2) application is seeking approval?

YES NO

(c) Is the listed drug(s) referenced by the application a pharmaceutical equivalent? YES NO

If “YES” to (c) and there are no additional pharmaceutical equivalents listed, proceed to question #12. If “NO” or if there are additional pharmaceutical equivalents that are not referenced by the application, list the NDA pharmaceutical equivalent(s); you do not have to individually list all of the products approved as ANDAs, but please note below if approved approved generics are listed in the Orange Book. Please also contact the (b)(2) review staff in the Immediate Office, Office of New Drugs. Pharmaceutical equivalent(s):

11) (a) Is there a pharmaceutical alternative(s) already approved (via an NDA or ANDA)?

(Pharmaceutical alternatives are drug products that contain the identical therapeutic moiety, or its precursor, but not necessarily in the same amount or dosage form or as the same salt or ester. Each such drug product individually meets either the identical or its own respective compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times and/or dissolution rates. (21 CFR 320.1(d)) Different dosage forms and strengths within a product line by a single manufacturer are thus pharmaceutical alternatives, as are extended-release products when compared with immediate- or standard-release formulations of the same active ingredient.) Note that for proposed combinations of one or more previously approved drugs, a pharmaceutical alternative must also be a combination of the same drugs.

YES NO

If “NO”, proceed to question #12.

(b) Is the pharmaceutical alternative approved for the same indication for which the 505(b)(2) application is seeking approval? YES NO

(c) Is the approved pharmaceutical alternative(s) referenced as the listed drug(s)?

YES NO

If “YES” and there are no additional pharmaceutical alternatives listed, proceed to question #12. If “NO” or if there are additional pharmaceutical alternatives that are not referenced by the application, list the NDA pharmaceutical alternative(s); you do not have to individually list all of the products approved as ANDAs, but please note below if approved generics are listed in



the Orange Book. Please also contact the (b)(2) review staff in the Immediate Office, Office of New Drugs.

Pharmaceutical alternative(s): Fentora (N 021947), Onsolis (N 022266), and generics for referenced drug, Actiq.

PATENT CERTIFICATION/STATEMENTS

12) List the patent numbers of all unexpired patents listed in the Orange Book for the listed drug(s) for which our finding of safety and effectiveness is relied upon to support approval of the (b)(2) product.

Listed drug/Patent number(s):

No patents listed proceed to question #14 13) Did the applicant address (with an appropriate certification or statement) all of the unexpired

patents listed in the Orange Book for the listed drug(s) relied upon to support approval of the (b)(2) product?

YES NO If “NO”, list which patents (and which listed drugs) were not addressed by the applicant.

Listed drug/Patent number(s):

14) Which of the following patent certifications does the application contain? (Check all that apply and identify the patents to which each type of certification was made, as appropriate.)

No patent certifications are required (e.g., because application is based solely on published literature that does not cite a specific innovator product)

21 CFR 314.50(i)(1)(i)(A)(1): The patent information has not been submitted to

FDA. (Paragraph I certification)

21 CFR 314.50(i)(1)(i)(A)(2): The patent has expired. (Paragraph II certification)

Patent number(s): 4 671 953 4 863 737

21 CFR 314.50(i)(1)(i)(A)(3): The date on which the patent will expire. (Paragraph

III certification)

Patent number(s): Expiry date(s): 21 CFR 314.50(i)(1)(i)(A)(4): The patent is invalid, unenforceable, or will not be

infringed by the manufacture, use, or sale of the drug product for which the application is submitted. (Paragraph IV certification). If Paragraph IV certification was submitted, proceed to question #15.



21 CFR 314.50(i)(3): Statement that applicant has a licensing agreement with the

NDA holder/patent owner (must also submit certification under 21 CFR 314.50(i)(1)(i)(A)(4) above). If the applicant has a licensing agreement with the NDA holder/patent owner, proceed to question #15.

21 CFR 314.50(i)(1)(ii): No relevant patents.

21 CFR 314.50(i)(1)(iii): The patent on the listed drug is a method of use patent and the labeling for the drug product for which the applicant is seeking approval does not include any indications that are covered by the use patent as described in the corresponding use code in the Orange Book. Applicant must provide a statement that the method of use patent does not claim any of the proposed indications. (Section viii statement)

Patent number(s): Method(s) of Use/Code(s):

15) Complete the following checklist ONLY for applications containing Paragraph IV certification and/or applications in which the applicant and patent holder have a licensing agreement:

(a) Patent number(s): (b) Did the applicant submit a signed certification stating that the NDA holder and patent

owner(s) were notified that this b(2) application was filed [21 CFR 314.52(b)]? YES NO

If “NO”, please contact the applicant and request the signed certification.

(c) Did the applicant submit documentation showing that the NDA holder and patent owner(s) received the notification [21 CFR 314.52(e)]? This is generally provided in the form of a registered mail receipt.

YES NO If “NO”, please contact the applicant and request the documentation.

(d) What is/are the date(s) on the registered mail receipt(s) (i.e., the date(s) the NDA holder

and patent owner(s) received notification):

Date(s):

(e) Has the applicant been sued for patent infringement within 45-days of receipt of the notification listed above?

Note that you may need to call the applicant (after 45 days of receipt of the notification) to verify this information UNLESS the applicant provided a written statement from the notified patent owner(s) that it consents to an immediate effective date of approval.

YES NO Patent owner(s) consent(s) to an immediate effective date of

approval











Sullivan, Matthew

From: Sullivan, MatthewSent: Wednesday, June 15, 2011 1:31 PMTo: Ann Tunstall; 'Michael Perelman'; Jackie MitchellSubject: Carton and container comments, NDA 22569

Page 1 of 1

6/15/2011

Please find below several comments regarding your June 1, 2011, submission:

A. General Comments for all container labels and carton labeling 1. The established name lacks prominence. Increase the font weight of the established name and ensure

it has a prominence commensurate with the prominence of the proprietary name, taking into account all pertinent factors including typography, layout, contrast and other printing features per 21CFR 201.10(g)(2).

2. The statement of strength is not prominent. Increase its prominence by increasing the font weight. B. Container Labels (100 mcg per spray and 400 mcg per spray)

1. The strengths are not well differentiated. Expand the color bar so that it includes the statement of strength.

2. The “Rx” symbol is too prominent. Unbold the font. 3. The distributor information is too prominent. Decrease the size of the statement “Distributed by

Archimedes Pharma”. C. Carton Labeling (100 mcg per spray and 400 mcg per spray), 1-count and 4-count

1. The medication guide statement “Dispense the enclosed Medication Guide to Each patient” is not prominent. Increase the prominence of the medication guide statement by increasing its font weight.

Thanks, Matt --- Matthew W. Sullivan, M.S. Senior Regulatory Project Manager Division of Anesthesia, Analgesia, and Addiction Products Food and Drug Administration Phone 301-796-1245 Fax 301-796-9723 [email protected]





2

a. For documents that have both paper and web versions, append only one version to the REMS, and include the other version in your Supporting Document.

b. Ensure that all documents listed above are also listed in the appropriate section of your REMS document (e.g. list the ) Note*: The is part of the materials; append it to your REMS, but it does not need to be listed in the REMS.

3. Re‐submission Instructions:

a. Once you have made all revisions that we have requested to date, to your REMS, REMS materials and Supporting Document, you should resubmit all your documents via e‐mail. We will review the materials to ensure that all revisions have been accurately incorporated, and that revisions you have proposed (if any) are acceptable. We will then notify when you may formally re‐submit via the Gateway.

b. Provide the REMS document and Supporting Document as two (2) separate PDF files:

• One file that includes the REMS document and all appended materials (see #2 above)

• One file that includes the REMS Supporting document (and remaining appended materials, as applicable)

c. Provide a clean WORD version of each individual document (provide the REMS and the REMS SD as two separate documents). If you are proposing any revisions to a document, also provide a redlined WORD version of the document that accurately reflects the proposed revisions.

d. Include the name of the document in document’s file name (e.g. prescriber overview)


(b) (4) (b) (4)

(b) (4)

23 PAGES OF DRAFT LABELING HAVE BEEN WITHHELD IN FULL AS b4 (CCI/TS) IMMEDIATELY FOLLOWING THIS PAGE




Sullivan, Matthew

From: Sullivan, MatthewSent: Monday, April 25, 2011 11:59 AMTo: 'Ann Tunstall'; 'Michael Perelman'Subject: N22569 Package Insert CommentsAttachments: 2d cycle version to Sponsor April 25 2011.doc

Page 1 of 1

4/25/2011

Attached are our comments on the PI. For the most part, we accepted your most recent changes. In a few places, there were a lot of changes, and I left those tracked simply so you could see what all the changes were. Please accept all those you agree with. Please take a look at the formatting and fix the areas where it needs it. Thanks, Matt --- Matthew W. Sullivan, M.S. Senior Regulatory Project Manager Division of Anesthesia, Analgesia, and Addiction Products Food and Drug Administration Phone 301-796-1245 Fax 301-796-9723 [email protected]






Sullivan, Matthew

From: Sullivan, MatthewSent: Friday, April 15, 2011 1:43 PMTo: 'Michael Perelman'; Ann TunstallSubject: N 22569 protocol comments

Page 1 of 2

4/15/2011

Hello – Please find below our comments on the labeling comprehension study. Let me know if you have any questions. Matt

General Comments for Study Design 1. We acknowledge the study assesses user tasks; however, you did not submit a risk

assessment that defined all of the critical user tasks needed for a patient to use Lazanda safely, nor do you define the clinical impact that failure of these user tasks could incur. Ensure a complete risk assessment is included in the study protocol.

2. There is no indication that the Instructions for Use have been screened to determine the literacy level at which they were written. Determine the literacy level at which the IFU is written. The recommended literacy level is sixth to eighth grade.

3. According to the study design, up to 30 adult men and women will be recruited for the study so it is unclear what the intended goal is concerning the number of participants in the study. State the minimum number of participants that will be included in the study to ensure there are enough participants.

4. The study protocol does not state what will be done with the data once it is collected or how it will be used to revise the Instructions for Use. We recommend that revisions be made to the IFU based on the results obtained from the study in order to determine the best presentation of the information to optimize the safe use of Lazanda.

5. Provide the rationale for excluding patients with brain cancer or current use of intrathecal or epidural opioids.

Selection of Participants 6. Participant Recruitment: Approximately 5 to 7 participants will be interviewed and a

determination made as to whether the interview guide requires revision. If the interview guide is revised for use with the 23 to 25 participants that follow, the data obtained from those 5 to 7 participants should be evaluated separately from the remaining 25 to 27 participants in the study. Additionally, any changes made to the interview guide should be discussed and the rationale provided.

7. The Sociodemographic Form is completed at the end of the interview which may limit the ability to obtain a diverse population sample up front. Determine the sociodemographics up front during the participant selection process in order to ensure there is a diverse population representative of patients who will likely use Lazanda.

Data Collection 8. The Lazanda Use Observation Form does not ask participants what can be done to improve

the Instructions for Use or what improvements can be made to the product to make it easier to use. Include this question in the Lazanda Use Observation Form.

9. In the Lazanda Use Observation Form we note that in some of the steps the patient is given the option to “demonstrate or verbalize” the step. Verbalization, rather than demonstration, may not detect potential problems with carrying out that particular step and may hinder the


ability to gather useful data from the study. In all instances where the step can be physically demonstrated, have the participant demonstrate the step.

10. The Clinical Form does not ask how often the potential participant has breakthrough pain. Consider adding this question to the form to help screen potential participants.

Thanks, Matt --- Matthew W. Sullivan, M.S. Senior Regulatory Project Manager Division of Anesthesia, Analgesia, and Addiction Products Food and Drug Administration Phone 301-796-1245 Fax 301-796-9723 [email protected]

Page 2 of 2

4/15/2011Reference ID: 2934094







DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration Silver Spring MD 20993

NDA 022569 REVIEW EXTENSION – MAJOR AMENDMENT

Archimedes Development Limited c/o SciLucent, LLC 585 Grove St, Suite 300 Herndon, VA 20170 Attention: Ann Tunstall, PhD Managing Consultant Dear Dr. Tunstall: Please refer to your New Drug Application (NDA) submitted August 30, 2009, received August 31, 2009, under section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FDCA) for fentanyl citrate nasal spray, 100 and 400 mcg. On March 24, 2011, we received your March 24, 2011, solicited major amendment to this application. The receipt date is within three months of the user fee goal date. Therefore, we are extending the goal date by three months to provide time for a full review of the submission. The extended user fee goal date is June 30, 2011. In addition, we are establishing a new timeline for communicating labeling changes and/or postmarketing requirements/commitments in accordance with “PDUFA REAUTHORIZATION PERFORMANCE GOALS AND PROCEDURES – FISCAL YEARS 2008 THROUGH 2012.” If major deficiencies are not identified during our review, we plan to communicate proposed labeling and, if necessary, any postmarketing requirement/commitment requests by June 16, 2011. If you have any questions, call Matt Sullivan, Regulatory Project Manager, at 301-796-1245.

Sincerely, {See appended electronic signature page} Sara E. Stradley, MS Chief, Project Management Staff Division of Anesthesia, Analgesia and Addiction Products Office of Drug Evaluation II Center for Drug Evaluation and Research



SARA E STRADLEY03/29/2011


Sullivan, Matthew

From: Sullivan, MatthewSent: Friday, March 25, 2011 1:22 PMTo: 'Michael Perelman'Cc: Jackie Mitchell; Ann TunstallSubject: N22569 Lazanda pouch comments

Page 1 of 1

3/25/2011

Below are the comments on the pouch labeling. Carbon Pouch Labeling

1. For clarity, revise the statement “Disposable Pouch...” to read “Disposable Pouch for use only with Lazanda” or similar verbiage and delete the statement “For exclusive use.” Additionally, increase the prominence of the words “Disposable Pouch”.

2. Provide instructions on the front panel for how to seal the pouch. 3. The company name logo is prominent on the front panel. Decrease its size, relocate it to the back panel, or

delete it altogether. Thanks Matt





require proper sizing and alignment in the Medication Guide.

4. Most of our energy is spent on reviewing and editing the full prescribing info (FPI) section. If the FPI is discordant with another section (for example, the warnings are listed in a different order) you should assume that the FPI is correct and make the corresponding change in the highlights and table of contents section.

Done 5. There are some “notes to sponsor” in the label – either as inline text or as a tracked-change balloon

comment. If you can easily address the request/comment, you can do so without providing a written response. If you’d like to propose an alternate method of addressing our concern, it’s probably best to include that on a separate document so that the label doesn’t become too disorganized.

Responses have been given in comments annotated on the document. 6. We’ve done our best to provide all the changes and comments that we have at the moment, but the label

will continue to be reviewed going forward, so additional changes may be necessary. 7. Go ahead and replace the TRADENAME with Lazanda throughout. Done

Thanks, Matt --- Matthew W. Sullivan, M.S. Regulatory Project Manager Division of Anesthesia and Analgesia Products Food and Drug Administration Phone 301-796-1245 Fax 301-796-9722 / 9723 [email protected] *** CONFIDENTIALITY NOTICE *** This message and attachments are intended only for the use of the individual to whom it is addressed and may contain information that is confidential, privileged, or exempt from disclosure. If you are not the intended recipient, you are hereby notified that any discussion, distribution, or copying of this e-mail and attachments is strictly prohibited. If you have received this communication in error, please notify us immediately by phone or return e-mail and delete this e-mail and attachments without reading or copying. Thank you. Archimedes Pharma Limited: Registered and Head Office: 250 South Oak Way, Green Park, Reading RG2 6UG, United Kingdom. A company registered in England & Wales. Registered No: 530864

This email message has been delivered safely and archived online by Mimecast. A true SaaS solution, Mimecast provides the security, continuity and archiving for millions of emails, across thousands of customers every day. For more information please visit http://www.mimecast.co.uk

Page 5 of 5

3/25/2011









Sullivan, Matthew

From: Sullivan, MatthewSent: Friday, March 04, 2011 8:10 PMTo: 'Ann Tunstall'; 'Jackie Mitchell'Subject: N22569 carton and container comments

Page 1 of 2

3/4/2011

Jackie / Ann – Here are the comments regarding the carton and container labeling: A. General Comments for the Container Labels and Carton Labeling 1. Ensure the established name (which includes the active ingredient and dosage form) is printed in letters that are at least ½ as large as the letters comprising the proprietary name and that the established name has a prominence commensurate with the proprietary name, taking into account all pertinent factors, including typography, layout, contrast, and other printing features [21 CFR 201.10(g)(2)]. 2. We note the use of “100” and “400” on the container labels and carton labeling, which appear to represent the strength; however, this is an incomplete strength presentation and may be confusing because there is no unit of measure or other indicator of what the numbers represent. Therefore, revise the “100” and “400” to read: “100 mcg per spray” and “400 mcg per spray”. These statements may remain in their present locations. 3. The “Rx” portion of the “Rx only” statement is too large and distracting due to its prominence. Decrease the size of the “Rx” portion of the statement. B. Container Labels 1. As currently presented, the container labels appear crowded. Due to their limited size, ensure that the proprietary name, established name, and strength presentations are the most prominent information displayed. Consider removal of other unnecessary or less important information [see 21CFR 201.10(i)], but retain the statement “Return to child resistant container after use” and consider increasing its prominence since this statement is an important safeguard against accidental exposure. C. Carton Labeling 1. As currently presented, the on the principle display panel is large and distracting from more important information. We request you remove this . 2. Per 21CFR 201.10(d)(1), any statement of the quantity of an ingredient should be expressed per unit (e.g., per spray). The current statement

on the principle display panel is incomplete. Additionally, there is already a statement on the side panel that reads “Each 100 microlitre spray contains fentanyl citrate equivalent to 100 mcg fentanyl base.” Therefore, remove the statement on the principle display panel. Also change “microlitre” to read “microliter.” 3. The statement ” is confusing and incomplete. Revise this statement to read, “Each bottle delivers 8 full sprays. Each spray delivers 100 microliters of solution.”


(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)




Sullivan, Matthew

From: Sullivan, MatthewSent: Friday, March 04, 2011 5:13 PMTo: 'Jackie Mitchell'; Ann TunstallSubject: REMS comments N22569Attachments: Attachment A_110304a_Lazanda REMS Document_redline.pdf

Page 1 of 2

3/4/2011

Ann / Jackie –

We refer to the meeting held on October 28, 2010 and to the REMS notification letter for Lazanda dated November 12, 2010. We further refer to the teleconference on February 15, 2011, during which we communicated harmonizing the individual programs to facilitate the implementation of a single, shared system across all TIRF products. We also refer to the teleconference on March 03, 2011, in which we communicated the need for creation of additional REMS materials. We acknowledge receipt of your proposed REMS for Lazanda included in your submissions dated December 22, 2010, and January 31, 2011. In the Lazanda REMS, you have proposed changes that do not conform with the standardized materials. You have not provided adequate justification for these changes, and in the interest of standardization, we are requesting that you conform the REMS to the template as we requested originally. The attached redline reflects the changes that are needed to conform to the template. The comments below are based on the preliminary review of the Lazanda REMS and supporting materials. We hope you can provide replies quickly so that we can provide you final input on the REMS, REMS Materials and Supporting Document.

1. The REMS document has been revised to conform with the standardized materials. Please see Attachment A for a redlined version of the REMS document. NOTE: FDA has added text to the footer of this document, for document control purposes. This footer (red text) should be deleted in your final document.

2. As discussed in the February 15, 2011, teleconference, your proposed education program and

knowledge assessment will require modifications. We will be providing you with specific comments under a separate cover.

3. As discussed in the March 03, 2011, teleconference, Dear Healthcare Provider Letter and

Dear Pharmacist Letter distribution has been added to the REMS (under ETASU A and ETASU B, respectively). Refer to the Abstral REMS program ‘Dear Healthcare Provider Letter,’ ‘Dear Outpatient Pharmacy Letter,’ and ‘Dear Inpatient Pharmacy letter,’ create and submit these letters for the Lazanda REMS.

4. As discussed in the March 03, 2011, teleconference, REMS Program Overview materials are

needed to inform enrollees about REMS program requirements and operations. Refer to the Abstral REMS program’s “Prescriber Program Overview,” “Overview for Outpatient Pharmacies,” “Overview for Inpatient Pharmacies,” and “Overview for Patients & Caregivers,” and create and submit these materials for the Lazanda REMS program.

5. As discussed in the February 15, 2011, teleconference, please remove the option for





Sullivan, Matthew

From: Sullivan, MatthewSent: Thursday, March 03, 2011 8:52 PMTo: 'Ann Tunstall'Cc: 'Jackie Mitchell'; '[email protected]'Subject: N22569 Lazanda package insert + med guideAttachments: 2d cycle version to Sponsor.doc

Page 1 of 1

3/3/2011

Attached is a copy of the labeling changes for the PI + Med Guide. A few notes:

1. We tried to use tracked changes, but there is a possibility that some changes were made without it being turned on. You should assume that any deletion/addition made without being tracked is intentional, but you’re welcome to ask us if something doesn’t make sense.

2. As above, we’d like you to use tracked changes in your response(s). Changes in this document that you agree with should be ‘accepted’ so that the end result is a clean label. It’s most helpful if the only tracked changes that we see when we get the label back are the changes you’ve made (or changes that we have made which you don’t agree with).

3. We spend virtually no time worrying about formatting. Please update the label to ensure that the formatting is correct. (The exception to this is the med guide. We have tried to provide the med guide in the correct formatting.) Additionally, please ensure that all cross-links in the text are correct, and that sections headings all match between the various sections.

4. Most of our energy is spent on reviewing and editing the full prescribing info (FPI) section. If the FPI is discordant with another section (for example, the warnings are listed in a different order) you should assume that the FPI is correct and make the corresponding change in the highlights and table of contents section.

5. There are some “notes to sponsor” in the label – either as inline text or as a tracked-change balloon comment. If you can easily address the request/comment, you can do so without providing a written response. If you’d like to propose an alternate method of addressing our concern, it’s probably best to include that on a separate document so that the label doesn’t become too disorganized.

6. We’ve done our best to provide all the changes and comments that we have at the moment, but the label will continue to be reviewed going forward, so additional changes may be necessary.

7. Go ahead and replace the TRADENAME with Lazanda throughout. Thanks, Matt --- Matthew W. Sullivan, M.S. Regulatory Project Manager Division of Anesthesia and Analgesia Products Food and Drug Administration Phone 301-796-1245 Fax 301-796-9722 / 9723 [email protected]






Sullivan, Matthew

From: Sullivan, MatthewSent: Thursday, March 03, 2011 4:19 PMTo: 'Ann Tunstall'Subject: Micro Information Request N22569

Page 1 of 2

3/3/2011

Ann – Some additional microbiology requests. They’d like to get answers, if possible, to these tomorrow. I’m not sure if that’s possible, but if you could see what you can do, that would be appreciated. I should add that our mico reviewer is available for a t-con if necessary to discuss these. Thanks Matt (i) Please briefly describe how the B. cepacia strain used for validation (ATCC 25416) is cultured and maintained prior to being inoculated into 1:10 diluted product. (ii) Validation SOP 02588 states that testing for B. cepacia may involve a direct inoculation or filter method. (See detailed procedures below questions.) Please indicate which procedure will be used for routine testing. (iii) For validation the appearance of B. cepacia on OFPBL plates was confirmed by colony morphology (yellow green to blue green colonies with yellow halos). Will additional identification procedures be used during routine testing? Item 8.13.1 (page 15) of SOP 02588 states that verification might be implemented using a Vitek 2 automated identification system. (iv) The revised drug product specification table (Table 3.2.P.5.1-2) indicates DPT-SOP-00686 as one of the methodologies that will be used for microbial quality testing. Please provide a copy of this SOP or indicate its location in the submission. Direct Inoculation Method: (1) product is diluted 1:10 (10 mL to 90 mL) in trypticase soy broth (TSB); (2) 10 ml samples are aliquoted into test tubes; (3) the samples are incucated for 18 – 24 hours at 30 – 35oC; (3) samples of incubation mixture from each tube are streaked onto selective OFPBL plates; (4) the OFPBL plates are incubated for 4 – 7 days at 30 – 35oC and examined for B. cepacia colonies. Filter Method: 10 mL of 1:10 diluted product in TSB is immediately passed through a filter that is then applied to OFPBL plates. The latter are incucated for 4 – 7 days at 30 – 35oC and examined for B. cepacia colonies.


Thanks, Matt --- Matthew W. Sullivan, M.S. Regulatory Project Manager Division of Anesthesia and Analgesia Products Food and Drug Administration Phone 301-796-1245 Fax 301-796-9722 / 9723 [email protected]

Page 2 of 2

3/3/2011





Sullivan, Matthew

From: Sullivan, MatthewSent: Thursday, February 17, 2011 3:42 PMTo: 'Ann Tunstall'Subject: NDA 22569 Information Request

Page 1 of 1

3/1/2011

Ann – An information request from OSE:

We have reviewed the revised container closure system and continue to have safety concerns with its use. We note the following:

1. Post-marketing surveillance has indicated

greater patient comprehension occurs when the device . This message was conveyed to you in a pre-NDA meeting held on September 22, 2008.

2. It is possible to actuate a partial spray without causing the spray counter to advance. Therefore,

patients could potentially deliver multiple sprays without advancing the counter.

3. The carbon pouch must be kept until the bottle is used up. It is not clear how or where the pouch should be stored while the bottle is in use in order to prevent its exposure to children, pets, etc.

We recognize the audible “click” and visual advancement of the counter should help inform patients and caregivers that the dose has been delivered, however, this may not be sufficient for patients or caregivers who are impaired in these areas. Additionally, proper disposal of the priming sprays, unwanted extra sprays and residual fentanyl solution is important in order to protect household contacts from accidental exposure to the fentanyl solution. Therefore, we recommend you address the issues outlined above and then conduct a usability/labeling comprehension study with the revised device to determine if patients and caregivers are able to use and dispose of the product correctly using the instructions provided. We request that you respond to these issues in a timely manner so that we can continue the review of your application.

Thanks, Matt --- Matthew W. Sullivan, M.S. Regulatory Project Manager Division of Anesthesia and Analgesia Products Food and Drug Administration Phone 301-796-1245 Fax 301-796-9722 / 9723 [email protected]


(b) (4)

(b) (4)




DEPARTMENT OF HEALTH & HUMAN SERVICES

Public Health Service

Food and Drug Administration

Silver Spring, MD 20993

NDA 022569

PROPRIETARY NAME REQUEST - CONDITIONALLY ACCEPTABLE

Archimedes Development Limited c/o SciLucent, LLC 585 Grove Street, Suite 300 Herndon, Virginia 20170 ATTENTION: Ann Tunstall, Ph.D. US agent for Archimedes Dear Dr.Tunstall: Please refer to your New Drug Application (NDA) resubmission dated September 30, 2010, received September 30, 2010, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Fentanyl Nasal spray, 100 mcg per spray and 400 mcg per spray We also refer to your November 29, 2010, correspondence, received November 29, 2010, requesting review of your proposed proprietary name, Lazanda, and your December 10, 2010, amendment to the proprietary name request, received December 10, 2010. We have completed our review of the proposed proprietary name, Lazanda and have concluded that it is acceptable. If any of the proposed product characteristics as stated in your November 29, 2010 submission are altered prior to approval of the marketing application, the proprietary name should be resubmitted for review. If you have any questions regarding the contents of this letter or any other aspects of the proprietary name review process, contact Abolade (Bola) Adeolu, Safety Regulatory Project Manager in the Office of Surveillance and Epidemiology, at (301) 796-4264. For any other information regarding this application contact the Office of New Drugs (OND) Regulatory Project Manager, Matthew Sullivan at (301) 796-1245.

Sincerely, {See appended electronic signature page}

Carol Holquist, RPh Director Division of Medication Error Prevention and Analysis Office of Surveillance and Epidemiology Center for Drug Evaluation and Research



CAROL A HOLQUIST02/24/2011



Food and Drug Administration Silver Spring, MD 20993

NDA 022569

PRE-APPROVAL REMS NOTIFICATION Archimedes Development Limited c/o SciLucent, LLC 585 Grove St, Suite 300 Herndon, VA 20170 Attention: Ann Tunstall, PhD Managing Consultant Dear Dr. Tunstall: Please refer to your August 30, 2009, New Drug Application (NDA) submitted under section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FDCA) for fentanyl citrate nasal spray, 100 and 400 mcg. Section 505-1 of the FDCA authorizes FDA to require the submission of a Risk Evaluation and Mitigation Strategy (REMS), if FDA determines that such a strategy is necessary to ensure that the benefits of the drug outweigh the risks [section 505-1(a)]. In accordance with section 505-1 of the FDCA, we have determined that a REMS is necessary for fentanyl citrate nasal spray to ensure the benefits of the drug outweigh the risks of overdose, abuse, misuse, addiction, and serious complications due to medication errors. We further refer to the meeting held on October 28, 2010, at the FDA White Oak Campus, at which we discussed that in the interest of public health and to reduce the burden on the healthcare system of having multiple unique REMS programs, we have determined that a single, shared system should be used to implement the REMS for all members of the class. The necessary REMS elements should be implemented across the class of transmucosal immediate release fentanyl (TIRF) products to address the serious risks described above. We acknowledge receipt of your proposed REMS included in your Class 2 resubmission dated September 30, 2010. At the October 28, 2010 meeting, we informed the sponsors of the TIRF products of our development of standardized REMS materials that could be used in the development of a single shared system to implement the REMS for all TIRF products. At that meeting, we told sponsors that we intend to move rapidly to review and approve REMS for each of the TIRF products that include the standardized program, and we encouraged sponsors to work together to implement a single shared system to reduce the burden on the healthcare system of individual programs. This letter is a follow up to that meeting discussion.


NDA 022569 Page 2

Attachment 1 contains a REMS program that can be implemented as a single shared system across all TIRF products, and we recommend that your proposed REMS be revised to conform to this program. The program will include standardized elements and enrollment forms that can be used by all sponsors of TIRF products and can be implemented using existing pharmacy systems. Your revised proposed REMS must include the following:

Medication Guide: As one element of a REMS, FDA may require the development of a Medication Guide as provided for under 21 CFR 208. Pursuant to 21 CFR 208, FDA has determined that fentanyl citrate nasal spray poses a serious and significant public health concern requiring the distribution of a Medication Guide. The Medication Guide is necessary for patients’ safe and effective use of fentanyl citrate nasal spray. FDA has determined that fentanyl citrate nasal spray is a product for which patient labeling could help prevent serious adverse effects and that has serious risks of which patients should be made aware because information concerning these risks could affect patients’ decisions to use, or continue to use fentanyl citrate nasal spray. Under 21 CFR 208, you are responsible for ensuring that the Medication Guide is available for distribution to patients who are dispensed fentanyl citrate nasal spray. Elements to Assure Safe Use: We have determined that elements to assure safe use are necessary to mitigate serious risks listed in the labeling of the drug. In addition, we have determined that a Medication Guide and a communication plan are not sufficient to mitigate the serious risks. Your REMS must include tools to manage these risks, including at least the following:

− Healthcare providers are specially certified or trained − Pharmacies, practitioners, or health care settings that dispense the drug are

specially certified − The drug is dispensed to patients with evidence or other documentation of safe-

use conditions Implementation System: The REMS must include an implementation system to monitor and evaluate the implementation of the elements to assure safe use (outlined above) that require pharmacies, practitioners, or health care settings that dispense the drug be specially certified and the drug be dispensed to patients with documentation of safe use conditions. Include an intervention plan to address any findings of non-compliance with elements to assure safe use and to address any findings that suggest an increase in risk. The Implementation System must include all elements listed in Attachment 1. Timetable for Submission of Assessments: The proposed REMS must include a timetable for submission of assessments that shall be no less frequent than every six (6) months for the first year following the approval of the fentanyl citrate nasal spray REMS, and annually thereafter. You should specify the reporting interval (dates) that each assessment will cover and the planned date of submission to the FDA of the assessment.


NDA 022569 Page 3

To facilitate inclusion of as much information as possible while allowing reasonable time to prepare the submission, the reporting interval covered by each assessment should conclude no earlier than 60 days before the submission date for that assessment. For example, the reporting interval covered by an assessment that is to be submitted by July 31st should conclude no earlier than June 1st. Each assessment must assess the extent to which the elements to assure safe use of your REMS are meeting the goals of your REMS and whether the goals or elements should be modified.

This submission should include two parts: a “proposed REMS” and a “REMS supporting document.” Attached is a template for the proposed REMS that includes information that we believe is pertinent across the class of TIRF products (see Attachment 1). Additionally, all relevant proposed REMS materials including: enrollment forms, educational, and communication materials should be appended to the proposed REMS. These appended documents should also be standardized across the class of TIRF products, with the exception of the product-specific information that will be included in the training program for prescribers. Once FDA finds the content acceptable and determines that the application can be approved, we will include these documents as an attachment to the approval letter that includes the REMS. The REMS, once approved, will create enforceable obligations. The REMS supporting document should be a document explaining the rationale for each of the elements included in the proposed REMS (see Attachment 2). Before we can continue our evaluation of this supplement NDA, you will need to submit the revised proposed REMS. For administrative purposes, designate the proposed REMS submission “PROPOSED REMS for NDA 022569” and all subsequent submissions related to the proposed REMS “PROPOSED REMS-AMENDMENT for NDA 022569.” If you do not submit electronically, please send 5 copies of your REMS-related submissions. If you have any questions, call Matt Sullivan, Regulatory Project Manager, at 301-796-1245.

Sincerely, {See appended electronic signature page} Bob A. Rappaport, M.D. Director Division of Anesthesia and Analgesia Products Office of Drug Evaluation II Center for Drug Evaluation and Research









Silver Spring, MD 20857 NDA 022569 MEETING MINUTES Archimedes Development Limited c/o SciLucent, LLC 585 Grove St, Suite 300 Herndon, VA 20170 Attention: Ann Tunstall, PhD Managing Consultant Dear Dr. Tunstall: Please refer to your New Drug Application (NDA) dated August 30, 2009, received August 31, 2009, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for fentanyl citrate nasal spray, 100 and 400 mcg. We also refer to the August 24, 2010, meeting between representatives of your firm and the FDA. The purpose of the meeting was to discuss our June 30, 2010, Complete Response letter. A copy of the official minutes of the meeting is attached for your information. Please notify us of any significant differences in understanding regarding the meeting outcomes. If you have any questions, call me at (301) 796-1245.

Sincerely, {See appended electronic signature page} Matthew W. Sullivan, MS Regulatory Project Manager Division of Anesthesia and Analgesia Products Office of Drug Evaluation II Center for Drug Evaluation and Research

Enclosure: Meeting Minutes

NDA 022569 Page 3 Background: The Division’s responses to the questions from the August 9, 2010, meeting package were sent to the Sponsor on August 23, 2010. Presented below are the Division’s comments and responses to questions in the background meeting package. The Sponsor’s questions are listed in italics, with Agency responses and comments in bold. Discussion that took place at the meeting is captured in normal text following the question to which it pertains. After introductions, the conversation focused on the Division’s August 23, 2010, preliminary meeting responses. PRODUCT QUALITY Question 1. The container-closure system is inadequate to prevent accidental exposure to the

fentanyl solution by patients, caregivers, and household contacts.

a. The pump assembly can be removed from the glass bottle with moderate effort and no tools.

b. The top of the pump assembly can be easily separated from the bottom of the mechanism, allowing fentanyl solution to leak out.

• Can FDA confirm that the modified container-closure system addresses points 1(a) and

(b)?

• Does the FDA agree that the proposed data package on the modified pump described in Appendix 1 appears adequate to support the change?

Division Response: We note the modifications you have made to the device and, on face, the device appears more robust. Whether or not the changes will adequately address the deficiencies will be a review issue. In this vein, as part of your re-submission, provide samples of your re-designed to-be-marketed drug product containing placebo solution, including your proposed disposal pouch and child resistant container, as well as data to support your planned changes. Discussion: There was no discussion beyond the Division’s initial written response.

Post Meeting CMC Comment: In addition to data, other relevant information, such as descriptions of design changes (including engineering drawings), should be provided to support modifications of the device.

(b) (4)

NDA 022569 Page 4 Question 2. The container-closure system is inadequate to ensure an accurate accounting of

the number of sprays delivered.

a. If the top of the pump was removed and then replaced, it could be indexed at various positions along the dose counter and would no longer accurately reflect the number of sprays delivered.

b. It is possible to actuate a dose without causing the dose counter to advance.

• Does FDA agree that the modifications to the pump assembly described in Appendix 1 addresses both points 2(a) and 2(b) above?

• With regard to 2(b), can the FDA confirm the circumstance under which they found it possible to actuate a dose without causing the counter to advance?

Division Response: By modulating the force of actuation on the sample device you have provided, we were able to actuate a dose delivery without advancing the counter. We also note that this technique could defeat the purpose of the lock-out mechanism. Also see our response to Question 1. Discussion: The Sponsor noted that the amount of drug product that is able to be sprayed out of the device without advancing the dose indicator is less than a full dose. The Sponsor acknowledged that this is not an ideal situation, but they stated that this doesn’t cause a safety concern for patients. The Division replied that a partial dose is not a safety concern, but that if the patient realizes that the dose indicator didn’t advance, they may subsequently administer a full dose. The Division further noted that in many opioid-tolerant patients this would not be a safety concern, but that it would be an issue for internal discussion when the complete response resubmission was reviewed. The Sponsor noted that since one aspect of the REMS was to ensure that only opioid-tolerant patients were prescribed the product, that a patient receiving a full plus a partial dose should not be a cause for concern. The Division also stated that the redesigned device appeared sufficiently ‘hardened’ to prevent inadvertent or accidental opening. Question 3. The alternative method of disposal (disposing of priming/unwanted sprays of

fentanyl by spraying into an activated carbon cloth pouch), as proposed in Appendix 2, addresses FDA concerns and will protect household members from accidental exposure.

• Does the FDA agree in principle that the alternative proposal to dispose of priming/unwanted sprays of fentanyl by spraying into an activated carbon cloth pouch (that irreversibly absorbs the fentanyl) appears adequate to protect patients and household contacts from unintentional exposure?

NDA 022569 Page 5

• Does the FDA agree in principle that as a result of the alternative method for disposal of unwanted sprays, in conjunction with the improvements to the container/closure system described above and in Appendix 2, the disposal of the small volume of residual fentanyl left in the bottle by placing it in the CRC and throwing in the trash is adequate to protect patients and household contacts from unintentional exposure?

• Does the FDA agree that the proposed data package described in Appendix 2 to demonstrate that the activated carbon pouch is “fit for purpose” will be adequate to support its use?

Division Response: We note your proposed disposal method. While the pouch appears to be an improvement over what you proposed in the NDA, whether it is adequate will be a review issue. We suggest that you include at least two carbon cloth pouches per bottle, one pouch for the prime and one pouch for the unwanted sprays. Provide data to support an “expiry” to justify how long the pouch can be used effectively. The large quantity for the high concentration [4 mg/mL] solution) of residual fentanyl solution after maximal use has not been addressed. While your proposal may address concerns about unintentional exposure of patients and household contacts during priming and disposing of unused doses, it does not address the issue of large quantities of residual fentanyl solution in the community. This problem appears to be inherent in the product design. We recommend that you consider redesigning the device to inactivate the residual fentanyl after the 8th dose. Discussion: The Division asked the Sponsor if they would be able to provide two activated carbon cloth pouches with each vial, one for the priming doses, and one for any doses that many need to be discarded at the end of use. The Sponsor stated that they would prefer to provide a single pouch, and ensure that the patients are educated not to discard the pouch until they discard the vial. The Sponsor stated that the net fill weight per vial can’t be lowered below , otherwise the amount of drug product delivered in the last dose (dose 8) can’t be assured to be the same as the first dose. After 8 sprays, however, a small amount of drug product remains in the vial and in the spray mechanism. The Sponsor proposed that they could remove the current lockout after the 8th dose, and allow a patient to spray the remaining drug product into the pouch. The Division noted that this would not be ideal, since some patients would accidently or intentionally continue to use these diminishing doses. The Sponsor stated that patients could be educated to completely spray out their residual. The Division responded that we would need to be convinced that patients will actually do this, rather than patients simply demonstrating that they can do this, as would be evidenced in a traditional clinical trial. The Sponsor stated that this education would be an integral part of their provider-patient education. The Division expressed our concern that having any amount of extra fentanyl in the vial after the 8th use is worrisome. The Division encouraged the Sponsor to continue to investigate the possibilities of chemically inactivating the fentanyl after the last dose.

(b) (4)

(b) (4)

NDA 022569 Page 8 REMS Question 7. Archimedes is about to initiate the commercial build of the Elements To Assure

Safe Use proposed in its REMS. Can FDA identify any areas in the proposed REMS program about which the agency has any remaining concerns and/or major comments?

Division Response: This product, as well as all transmucosal immediate-release fentanyl products, will require a Risk Evaluation and Mitigation Strategy (REMS). We are currently working to create a more standardized REMS for this class of products. In the meantime, your REMS must include the following elements: Medication Guide, Elements to Assure Safe Use, Implementation System and Timetable for Submission of Assessments. Your REMS must also address proper disposal of residual fentanyl with your product, prescribing to opioid-tolerant patients only, appropriate dosing of these fentanyl products, and surveillance for misuse and abuse. You must submit a complete REMS at the time of your resubmission. Submit your REMS and REMS Supporting Document with your NDA resubmission as well as all planned materials identified within the proposed REMS that will be necessary to implement your proposal. Education should emphasize the safety messages important for safe use of the product. Product marketing materials generally are not appropriate to educate about product risks. We request that, to the extent possible, you work with the other manufacturers of transmucosal immediate-release fentanyl products. In order to minimize the burden on the healthcare system and its various stakeholders, we recognize the importance of having one shared REMS system for all of these products, not just a REMS for an innovator and its generics. Discussion: The Division stated that the burden of REMS on the healthcare system is an Agency concern. Any REMS, taken alone, would likely have a minimal effect on prescribers and pharmacists. However, when the requirements from all approved REMS are taken together, the Agency is concerned that the healthcare system may be completely overburdened. The Division noted that we are trying to standardize REMS to the extent possible, and are interested in a system where prescribers and pharmacists would interact with a single system which would appear very similar for all drugs, but the underlying processes may be implemented differently by Sponsors. The Division noted that we hope that various forms that are commonly used in REMS programs could be standardized in the next 6 to 12 months.




Version: 9/9/09 10

Reviewer:

Sheetal Argawal Y Clinical Pharmacology

TL:

Suresh Doddapaneni N

Reviewer:

David Petullo Y Biostatistics

TL:

Dionne Price Y

Reviewer:

Beth Bolan N Nonclinical (Pharmacology/Toxicology)

TL:

Dan Mellon Y

Reviewer:

Statistics (carcinogenicity)

TL:

Reviewer:

Immunogenicity (assay/assay validation) (for BLAs/BLA efficacy supplements) TL:

Reviewer:

Shelly Markofsky Y Product Quality (CMC)

TL:

Danae Christodoulou Y

Reviewer:

Quality Microbiology (for sterile products)

TL:

Reviewer:

CMC Labeling Review (for BLAs/BLA supplements)

TL:

Reviewer:

Facility Review/Inspection

TL:

Reviewer:

OSE/DMEPA (proprietary name)

TL:

Reviewer:

OSE/DRISK (REMS)

TL:

Reviewer:

Bioresearch Monitoring (DSI)

TL:

Version: 9/9/09 12

• If the application is affected by the AIP, has the

division made a recommendation regarding whether or not an exception to the AIP should be granted to permit review based on medical necessity or public health significance?

Comments:

Not Applicable YES NO

CLINICAL MICROBIOLOGY Comments:

Not Applicable FILE REFUSE TO FILE

Review issues for 74-day letter

CLINICAL PHARMACOLOGY Comments:



• Clinical pharmacology study site(s) inspections(s) needed?

YES NO

BIOSTATISTICS Comments:



NONCLINICAL (PHARMACOLOGY/TOXICOLOGY) Comments: Genetox studies not submitted. Will notify in 74-day letter.



IMMUNOGENICITY (BLAs/BLA efficacy supplements only) Comments:



PRODUCT QUALITY (CMC)


Version: 9/9/09 13

Comments: Review issues for 74-day letter

Version: 9/9/09 14

Environmental Assessment • Categorical exclusion for environmental assessment

(EA) requested? If no, was a complete EA submitted?

If EA submitted, consulted to EA officer (OPS)?

Comments:

Not Applicable

YES NO

YES NO

YES NO

Quality Microbiology (for sterile products) • Was the Microbiology Team consulted for validation

of sterilization? (NDAs/NDA supplements only) Comments: (via ONDQA)

Not Applicable

YES NO

Facility Inspection • Establishment(s) ready for inspection? Establishment Evaluation Request (EER/TBP-EER)

submitted to DMPQ?

Comments: (via ONDQA)

Not Applicable

YES NO

YES NO

Facility/Microbiology Review (BLAs only) Comments:



CMC Labeling Review (BLAs/BLA supplements only) Comments:


Version: 9/9/09 16

Appendix A (NDA and NDA Supplements only)

NOTE: The term "original application" or "original NDA" as used in this appendix denotes the NDA submitted. It does not refer to the reference drug product or "reference listed drug." An original application is likely to be a 505(b)(2) application if:

(1) it relies on published literature to meet any of the approval requirements, and the applicant does not have a written right of reference to the underlying data. If published literature is cited in the NDA but is not necessary for approval, the inclusion of such literature will not, in itself, make the application a 505(b)(2) application,

(2) it relies for approval on the Agency's previous findings of safety and efficacy for a listed drug product and the applicant does not own or have right to reference the data supporting that approval, or

(3) it relies on what is "generally known" or "scientifically accepted" about a class of products to support the safety or effectiveness of the particular drug for which the applicant is seeking approval. (Note, however, that this does not mean any reference to general information or knowledge (e.g., about disease etiology, support for particular endpoints, methods of analysis) causes the application to be a 505(b)(2) application.)

Types of products for which 505(b)(2) applications are likely to be submitted include: fixed-dose combination drug products (e.g., heart drug and diuretic (hydrochlorothiazide) combinations); OTC monograph deviations (see 21 CFR 330.11); new dosage forms; new indications; and, new salts. An efficacy supplement can be either a (b)(1) or a (b)(2) regardless of whether the original NDA was a (b)(1) or a (b)(2).

An efficacy supplement is a 505(b)(1) supplement if the supplement contains all of the information needed to support the approval of the change proposed in the supplement. For example, if the supplemental application is for a new indication, the supplement is a 505(b)(1) if:

(1) The applicant has conducted its own studies to support the new indication (or otherwise owns or has right of reference to the data/studies),

(2) No additional information beyond what is included in the supplement or was embodied in the finding of safety and effectiveness for the original application or previously approved supplements is needed to support the change. For example, this would likely be the case with respect to safety considerations if the dose(s) was/were the same as (or lower than) the original application, and.

(3) All other “criteria” are met (e.g., the applicant owns or has right of reference to the data relied upon for approval of the supplement, the application does not rely

Version: 9/9/09 17

for approval on published literature based on data to which the applicant does not have a right of reference).

An efficacy supplement is a 505(b)(2) supplement if:

(1) Approval of the change proposed in the supplemental application would require data beyond that needed to support our previous finding of safety and efficacy in the approval of the original application (or earlier supplement), and the applicant has not conducted all of its own studies for approval of the change, or obtained a right to reference studies it does not own. For example, if the change were for a new indication AND a higher dose, we would likely require clinical efficacy data and preclinical safety data to approve the higher dose. If the applicant provided the effectiveness data, but had to rely on a different listed drug, or a new aspect of a previously cited listed drug, to support the safety of the new dose, the supplement would be a 505(b)(2),

(2) The applicant relies for approval of the supplement on published literature that is based on data that the applicant does not own or have a right to reference. If published literature is cited in the supplement but is not necessary for approval, the inclusion of such literature will not, in itself, make the supplement a 505(b)(2) supplement, or

(3) The applicant is relying upon any data they do not own or to which they do not have right of reference.

If you have questions about whether an application is a 505(b)(1) or 505(b)(2) application, consult with your OND ADRA or OND IO.

ApplicationType/Number

SubmissionType/Number Submitter Name Product Name

-------------------- -------------------- -------------------- ------------------------------------------NDA-22569 ORIG-1 ARCHIMEDES

DEVELOPMENTLTD

(fentanyl nasal spray)



(b) (4)




Silver Spring, MD 20993

NDA 022569

PROPRIETARY NAME REQUEST WITHDRAWN

Archimedes Development Limited c/o SciLucent, LLC 585 Grove Street, Suite 300 Herndon, Virginia 20170 ATTENTION: Ann C. Tunstall, PhD US Agent to Archimedes Dear Dr. Tunstall: Please refer to your New Drug Application (NDA), submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Fentanyl Nasal Spray, 100 mcg per spray and 400 mcg per spray. We acknowledge receipt of your April, 7, 2010 correspondence, on April 10, 2010, notifying us that you are withdrawing your January 21, 2010 request for a review of the proposed proprietary name . This proposed proprietary name request is considered withdrawn as of April 7, 2010. If you have any questions regarding the contents of this letter or any other aspects of the proprietary name review process, call Bola Adeolu, Regulatory Project Manager in the Office of Surveillance and Epidemiology, at (301) 796-4264. For any other information regarding this application, contact the Office of New Drugs (OND) Regulatory Project Manager, Matthew Sullivan at (301) 796-1245.



(b) (4)




DEVELOPMENTLTD




(b) (4)


Food and Drug Administration Silver Spring, MD 20993

NDA 022569 INFORMATION REQUEST

Archimedes Development Limited c/o SciLucent, LLC 585 Grove St, Suite 300 Herndon, VA 20170 Attention: Ann Tunstall, PhD Managing Consultant Dear Dr. Tunstall: Please refer to your New Drug Application (NDA) dated August 30, 2009, received August 31, 2009, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for fentanyl nasal spray, 100 and 400 mcg. We are reviewing the Chemistry, Manufacturing and Controls section of your submission and have the following comments and information requests. We request a prompt written response in order to continue our evaluation of your NDA.

Container Closure System We have found that the top part of your pump (the nasal spray actuator) could be readily pulled off from the counter ring assembly. In doing so, a small amount of the solution came in contact with our hands. This would be a concern if the solution contained fentanyl. Subsequently, we noted that the actuator could be placed back in different positions relative to the counter ring assembly such that different numbers or colored marking could be seen in the indication window. If this scenario were to occur, the patient might not know how many priming strokes may be needed or the number of doses that have been administered. Accordingly, changes to the device may be necessary to address these concerns.

Additionally, three of our staff members were able to unscrew the pump assembly from three separate glass bottles of your (placebo filled) to-be-marketed drug product. They were able to unscrew the assembly with their bare hands and without the use of any tools. Since opened bottles of your fentanyl solutions are both a safety and abuse concern to the Agency, it may be necessary to modify your drug product so that the pump assembly can not be unscrewed from the bottles. You are also advised that any changes to the container/closure system, such as discussed above, may require changes to your NDA. For example, specification and spray characteristic changes or additional stability studies may be necessary. In addition, if

NDA 022569 Page 2

modifications are made, you should provide actual samples of the modified to-be-marketed drug product filled with the placebo solution to the Agency for our evaluation.

Methods Validation Data

In accordance with the appropriate sections of ICH Q2A and Q2B, provide the raw data and an adequate description of the methods used to support the validation of your method for the determination of in your drug substance. The raw data is requested to support the conclusions summarized in Table 3.2.S.4.3-1 of the original submission and the LOD and LOQ findings reported in the 2-17-10 amendment.

If you have any questions, call Matt Sullivan, Regulatory Project Manager, at 301-796-1245.

Sincerely, {See appended electronic signature page} Sara E Stradley, MS Chief, Project Management Staff Division of Anesthesia and Analgesia Products Office of Drug Evaluation II Center for Drug Evaluation and Research

(b) (4)




DEVELOPMENTLTD




(b) (4)

NDA 022569 Page 3

decision on the information reviewed and should not be construed to do so. These comments are preliminary and subject to change as we finalize our review of your application. In addition, we may identify other information that must be provided before we can approve this application. If you respond to these issues during this review cycle, depending on the timing of your response, and in conformance with the user fee reauthorization agreements, we may not be able to consider your response before we take an action on your application during this review cycle. If you have any questions, call Matt Sullivan, Regulatory Project Manager, at 301-796-1245.

Sincerely, {See appended electronic signature page} Sara E Stradley, MS Chief, Project Management Staff Division of Anesthesia and Analgesia Products Office of Drug Evaluation II Center for Drug Evaluation and Research




DEVELOPMENTLTD




(b) (4)



NDA 22-569 INFORMATION REQUEST

Archimedes Development Limited c/o SciLucent, LLC 585 Grove St, Suite 300 Herndon, VA 20170 Attention: Ann Tunstall, PhD Managing Consultant Dear Dr. Tunstall: Please refer to your new drug application (NDA) dated August 30, 2009, received August 31, 2009, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act, for Fentanyl nasal spray, 100 and 400 mcg. We are reviewing the Chemistry, Manufacturing, and Controls sections of your submission and have the following comments and information requests. We request a prompt written response in order to continue our evaluation of your NDA.

1. Provide a commitment to test for Burkholderia cepacia in the USP purified water used . The commitment should include the testing method.

2. Provide a description of the method for recovering and identifying "objectionable

microorganisms" as stated in the revised drug specifications (Table 3.2.P.5.1-2). The methods should include specific procedures for recovery and identification of B. cepacia.

If you have any questions, call Don Henry, Regulatory Project Manager, at (301) 796-4227.

Sincerely, {See appended electronic signature page} Prasad Peri, Ph.D. Acting Branch Chief Division of Pre-Marketing Assessment I Office of New Drug Quality Assessment Center for Drug Evaluation and Research

(b) (4)




DEVELOPMENTLTD



PRASAD PERI03/08/2010

(b) (4)




DEVELOPMENTLTD




(b) (4)



NDA 22-569 INFORMATION REQUEST

Archimedes Development Limited c/o SciLucent, LLC 585 Grove St, Suite 300 Herndon, VA 20170 Attention: Ann Tunstall, PhD Managing Consultant Dear Dr. Tunstall: Please refer to your new drug application (NDA) dated August 30, 2009, received August 31, 2009, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act, for Fentanyl nasal spray, 100 and 400 mcg. We are reviewing the Chemistry, Manufacturing, and Controls sections of your submission and have the following comments and information requests. We request a prompt written response in order to continue our evaluation of your NDA.

1. For each drug product component (Fentanyl citrate, mannitol, phenyethyl alcohol, propylparaben, HCl, sodium hydroxide, purified water), please provide:

a. Certificates of analysis; b. Microbiological acceptance criteria; c. Controls, tests and/or criteria determining absence from Burkholderia cepacia

contamination.

2. Please amend the Microbial Quality section of the drug product specifications (Table 3.2.P.5.1-2) to include absence of Burkholderia cepacia. The specification should include the B. cepacia detection method.

If you have any questions, call Don Henry, Regulatory Project Manager, at (301) 796-4227.

Sincerely, {See appended electronic signature page} Prasad Peri, Ph.D. Acting Branch Chief Division of Pre-Marketing Assessment I Office of New Drug Quality Assessment Center for Drug Evaluation and Research




DEVELOPMENTLTD

FENTANYL NASAL SPRAY


PRASAD PERI01/27/2010

NDA 022569 Page 2 If you intend to have a proprietary name for this product, we recommend that you submit a new request for a proposed proprietary name review. (See the draft Guidance for Industry, Complete Submission for the Evaluation of Proprietary Names, HTTP://www.fda.gov/cder/guidance/7935dft.pdf and “PDUFA Reauthorization Performance Goals and Procedures Fiscal Years 2008 through 2012”.) If you have any questions regarding the contents of this letter or any other aspects of the proprietary name review process, contact Bola Adeolu, Safety Regulatory Project Manager in the Office of Surveillance and Epidemiology, at (301) 796-4264. For any other information regarding this application contact the Office of New Drugs (OND) Regulatory Project Manager, Matthew Sullivan at (301) 796-1245.






DEVELOPMENTLTD




NDA 022569 Page 2

carcinogenic. In the absence of adequate justification, must be regulated to a level of NMT 1.5 mcg/day in the drug substance and drug product.

We recognize that there are literature reports suggesting that

Significant metabolites are generally deemed adequately qualified for safety. Include in the justification mentioned above a quantitative assessment of as a human metabolite at the maximum daily dose of fentanyl for your product. This assessment may include a literature review and copies of referenced citations. The presence of as a human metabolite at significant levels could render the need for qualification unnecessary.

Please be advised that as a 505(b)(2) submission, which relies on the Agency’s previous findings of safety and efficacy, we can not legally use information contained within a Summary Basis of Approval to support your application unless you have right of reference to the underlying data.

We are providing the above comments to give you preliminary notice of potential review issues. Our filing review is only a preliminary evaluation of the application and is not indicative of deficiencies that may be identified during our review. Issues may be added, deleted, expanded upon, or modified as we review the application. If you have not already done so, you must submit the content of labeling [21 CFR 314.50(l)(1)(i)] in structured product labeling (SPL) format as described at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. The content of labeling must be in the Prescribing Information (physician labeling rule) format. Please respond only to the above requests for additional information. While we anticipate that any response submitted in a timely manner will be reviewed during this review cycle, such review decisions will be made on a case-by-case basis at the time of receipt of the submission. REQUIRED PEDIATRIC ASSESSMENTS Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration are required to contain an assessment of the safety and effectiveness of the product for the claimed indication in pediatric patients unless this requirement is waived, deferred, or inapplicable. We acknowledge receipt of your request for a partial waiver as well as a partial deferral of pediatric studies for this application. Once we have reviewed your request, we will notify you if this request is denied.

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NDA 022569 Page 3

If you have any questions, call Matt Sullivan, Regulatory Project Manager, at 301-796-1245.

Sincerely, {See appended electronic signature page} Bob A. Rappaport, M.D. Director Division of Anesthesia, Analgesia and Rheumatology Products Office of Drug Evaluation II Center for Drug Evaluation and Research




DEVELOPMENTLTD




Sullivan, Matthew

From: Sullivan, MatthewSent: Friday, November 06, 2009 9:45 AMTo: 'Ann Tunstall'Subject: Clinical Infomation Request, 6 Nov 09

Page 1 of 1

6/28/2010

Hi Ann – Please address: In the list of study sites for study CP043/06/FCNS attached to the cover letter for the initial NDA submission, there are listings for site 913 (Leung) and 914 (Wallace). However, in the study report for CP043/06/FCNS, there is no site 914 (Wallace), but he is listed as a sub investigator for site 913. Provide clarification for this discrepancy. Also provide the number screened, number of screen failures, number of subjects entering titration, number of subjects randomized, number of premature discontinuations, and number of protocol violations if they are different than those presented in the table. Matt --- Matthew W. Sullivan, M.S. Regulatory Project Manager Division of Anesthesia, Analgesia and Rheumatology Products Food and Drug Administration Phone 301-796-1245 Fax 301-796-9722 / 9723 [email protected]

Sullivan, Matthew

From: Sullivan, MatthewSent: Monday, November 23, 2009 6:36 PMTo: 'Ann Tunstall'Subject: t IR

Page 1 of 1

6/28/2010

Ann – Thanks for the link you provided earlier today to the table. Please find below an additional request:

Please provide a table with the frequency of types of cancer in the subjects in study CP043

Thanks matt --- Matthew W. Sullivan, M.S. Regulatory Project Manager Division of Anesthesia, Analgesia and Rheumatology Products Food and Drug Administration Phone 301-796-1245 Fax 301-796-9722 / 9723 [email protected]

(b) (4)

Sullivan, Matthew

From: Sullivan, MatthewSent: Monday, November 23, 2009 12:17 PMTo: 'Ann Tunstall'Subject: information request 22569

Page 1 of 1

6/28/2010

Ann – In Section 11.2.2 (Page 66 of the PDF file) of the report for Study CPO43, there is a reference to Section 16.2.4.1. See below:

11.2.2 Medical History Past and current medical conditions are listed by patient in Listing 16.2.4.1.

Unfortunately, we can not locate this section in your application. Provide the location of this section so that we can locate the past and current medical conditions of the enrolled subjects, specifically the type of cancer. If this section is not in the submission, submit it as an amendment to the NDA. Thanks matt --- Matthew W. Sullivan, M.S. Regulatory Project Manager Division of Anesthesia, Analgesia and Rheumatology Products Food and Drug Administration Phone 301-796-1245 Fax 301-796-9722 / 9723 [email protected]

(b) (4)

Sullivan, Matthew

From: Sullivan, MatthewSent: Friday, January 08, 2010 3:54 PMTo: Ann TunstallSubject: intranasal fentanyl N022569

Page 1 of 3

6/28/2010

Ann – Here is a CMC info request. Please note that the request for samples (Comment #1) are not a request for addition samples. However, we do request a single disassembled product. Thanks, and please let me know if you have any questions. Matt We are reviewing the Chemistry, Manufacturing and Controls section of your NDA 022569 for your Fentanyl Nasal Spray, and we have the following comments and information requests. We request a prompt written response in order to continue our evaluation of your NDA.

1. Provide four actual samples of your proposed drug product filled with placebo solution. In addition, provide the disassembled components of your spray pump.

2. Provide evidence that your proposed drug product is in compliance with

3. In accordance with the FDA Guidance for Industry, related to nasal sprays, provide a specification (range) for the viscosity of your drug product solution to be used for the release of your nasal spray and as part of your post-approval stability protocol. Your proposed range should be justified, and your viscosity procedure should be validated.

4. For your release testing and post-approval stability protocol, provide and justify a range for

your gel strength specification.

5. Provide the Limit of Detection (LOD) and the Limit of Quantitation (LOQ) for in your method for the determination of this Related

Substance impurity in your fentanyl (drug substance).

6. Provide Appendices A, B, and C for your report entitled “Assay Qualification of the Related Substance Method for in Fentanyl API , P/N 161044, by HPLC”.

7. Since particles from your drug product that have a very small particle size can be inhaled

into the lungs, reinstitute a validated specification for the percentage of droplets that are less than . This specification should be used for the release and stability of your nasal spray and should be part of your post-approval stability protocol. Justify your upper limit (percent) from a safety point of view.

8. Your batch data (e.g. Section 3.2.P.5.4) show a much narrower range for D (max) in your

spray patterns than in your proposed specification range Accordingly, narrow

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your release and stability acceptance criteria for D (max).

9. Provide and up-date the stability specifications, including acceptance criteria, for the commercial batches that will be monitored according to your post-approval stability protocol.

10. Specify whether or not samples from future commercial batches in your post-approval

program will conform to Protocol no. 652001.001.014.

11. Amend your post-approval protocol to include testing for leachables ) at all time points.

12. Make your post-approval stability commitment for out-of-specification drug product. Use the

following or similar wording for this commitment :

“Archimedes Development Limited commits to withdraw from the market any lot found to fall outside the approved specifications for Fentanyl Nasal Spray. If the Archimedes has evidence that the deviation is a single occurrence that does not affect the safety or efficacy of the drug product, they will immediately discuss the failure with the FDA and provide justification for the continued distribution of the lot. Change or deterioration in a batch of Fentanyl Nasal Spray will be reported under 21 CFR 314.81(b)(1)(ii).”

Container/Closure

13. The proposed end-of-use lock has been implemented in the proposed commercial design. Clarify, if any nasal spray pumps of the proposed commercial design, which includes the end-of-use lock, have been tested in clinical trials, or in a patient in-use study.

14. Provide a description of the end-of-use lock, composition of components and engineering

drawings; alternatively, you may request from your DMF supplier(s) to identify the information, specific to the end-of-use lock applied to your product, in their DMF(s), amendments.

15. Provide a justification for the selection of the mechanical end-of-use lock versus other

physical and/or chemical methods to minimize residual fentanyl. You indicated that if the end-of-use lock is broken after the final actuation, of the residual volume can be recovered by repeatedly attempting to actuate the pump until no further drug product is delivered.

Labeling

16. The font of the established name on your container and carton labels is too small. This font must be at least one half the size of your proprietary (trade) name.

17. It is preferred that your established name read “(fentanyl) nasal spray” rather than “(fentanyl

nasal spray)”. 18. Provide the recommended storage conditions of your drug product in the HOW

SUPPLIED/STORAGE & HANDLING section (16.1) in your Annotated Draft Labeling text.

Page 2 of 3

6/28/2010

(b) (4)

(b) (4)

--- Matthew W. Sullivan, M.S. Regulatory Project Manager Division of Anesthesia, Analgesia and Rheumatology Products Food and Drug Administration Phone 301-796-1245 Fax 301-796-9722 / 9723 [email protected]

Page 3 of 3

6/28/2010

Sullivan, Matthew

From: Sullivan, MatthewSent: Thursday, January 28, 2010 2:40 PMTo: 'Ann Tunstall'Subject: REMS info request N22569

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Ann – These are preliminary REMS comments; as we continue our review, we will likely provide additional comments. Please respond to this request as soon as possible, and no later than February 11, 2010.

1. In order to complete our review, provide copies of the following materials: a. Prescriber training program and post-test b. Pharmacist training program (if different from above) c. All materials that will be enclosed with the letters sent as part of the Communication Plan

(e.g. the “Prescribing Information brochure” mentioned in the pharmacist letter). d. Website screen shots and copies of all materials that will be available as part of the REMS

on the website (as listed in Appendix D). We recommend a link off of the homepage to a REMS landing page. For example, the link could state: “Important Safety Information and Risk Evaluation and Mitigation Strategy (REMS)”, or “Healthcare Professionals click here for Risk Evaluation and Mitigation Strategy (REMS) information.” The landing page of the separate REMS link should then contain background information on the REMS, safety information, and the REMS materials. The webpage should not be a means to promote or any other Sponsor product.

2. Address the following questions concerning the

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Sullivan, Matthew

From: Sullivan, MatthewSent: Tuesday, February 02, 2010 4:38 PMTo: 'Ann Tunstall'Subject: Clinical info request N22569

Hi Ann -

Here is a clinical info request:

Study CP043: For patients who discontinued from the study prematurely who were coded as “other” provide further detail with regard to the actual reason(s) for discontinuation.

Also provide the classification for the pain pathophysiology (e.g. neuropathic, nociceptive, or mixed) for the patients studied.

Study CP044: For patients who discontinued from the study prematurely who were coded as “other” provide further detail with regard to the actual reason(s) for discontinuation.

Sullivan, Matthew

From: Sullivan, MatthewSent: Thursday, February 04, 2010 1:02 PMTo: 'Ann Tunstall'Subject: FW: NDA 22-569 fentanyl nasal spray IR

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Ann – Please submit race data for the subjects used in the Dose proportionality study # CP04205. The demographic data in the study report does not have that information. Thanks, matt

Sullivan, Matthew

From: Sullivan, MatthewSent: Thursday, February 18, 2010 4:47 PMTo: 'Ann Tunstall'Subject: Clinical Pharmacology IR N22569

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Ann – Late-breaking request from the Clin Pharm review team:

Please submit SAS (or Excel) data sets for studies CP04205, CP04707, and CP04807. We need these rather urgently. Thanks, Matt --- Matthew W. Sullivan, M.S. Regulatory Project Manager Division of Anesthesia, Analgesia and Rheumatology Products Food and Drug Administration Phone 301-796-1245 Fax 301-796-9722 / 9723 [email protected]

9. Provide copies of the manufacturer’s certificates of conformance (or equivalent certificates) for the nasal actuator, pump insert and counter ring in the NDA.

10. Provide data to demonstrate the stability of the various solutions (Working Standard, Working

Calibration, and Working Sample solutions) that are used for your Assay and Related Substances method by HPLC.

Thanks, Matt --- Matthew W. Sullivan, M.S. Regulatory Project Manager Division of Anesthesia, Analgesia and Rheumatology Products Food and Drug Administration Phone 301-796-1245 Fax 301-796-9722 / 9723 [email protected]

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